Gastro esophageal reflux disease (GERD) affects at least 40% of the population. Current treatments for GERD do not prevent reflux of gastric contents. Problems associated with GERD include the minor inconveniences of heartburn to the lethal complications of aspirational pneumonia in infancy and esophageal adenocarcinoma in adulthood. Our central hypothesis of this proposal is that a defect in the gastric clasp/sling muscle fiber complex is the underlying etiology of GERD. Our objectives are to identify receptors on the muscles and the nerves innervating these muscles that are implicated as causing GERD. Our focus is to use this information to develop new pharmacologic treatments targeting these receptors and impacting positively on the public health and health care expenditures. Aim 1: Test the hypothesis that GERD patients have different responses of the gastric sling/clasp muscle fiber complex than normal volunteers without GERD and that these responses result in reflux. We measure and compare differences between normal volunteers and GERD patients using two different approaches. The first approach uses simultaneous high-resolution ultrasonography and vector volume manometry before and after pharmacologic manipulation to inhibit the smooth muscle component (atropine) augment the smooth muscle component (bethanechol) or paralyze the skeletal muscle component (cisatracurium) of the GEJHPZ. The second approach uses simultaneous endoscopy and stationary high resolution manometry during gastric distension to determine the volume and pressure distension threshold for TLESRs before and after this pharmacologic manipulation. Aim 2: Test the hypothesis that both complete (Nissen) and 270: (Toupet) fundoplication procedures reduce reflux by strengthening the defective sling/clasp muscle fiber complex through tonic muscarinic receptor mediated tension of the gastric smooth muscle in the wrap of the fundoplication. We will compare GERD patients undergoing these 2 procedures to patients without GERD undergoing non-esophageal surgery. We will evaluate degree of GERD using both validated GERD questionnaires and Bravo(R) esophageal pH monitoring before surgery and at 1 and 3 months post operatively. GEJHPZ will be evaluated using: 1) simultaneous high-resolution ultrasonography and vector volume manometry with this pharmacologic manipulation and 2) simultaneous endoscopy and stationary high resolution manometry during gastric distension to determine volume and pressure distension threshold for TLESRs and temporal sequence of opening of the various components of the GEJHPZ. Aim 3: Test the hypothesis that there is a difference in contractility of the gastric sling/clasp muscle fiber complex between subjects with and without GERD. We compare the neurotransmitters and receptors responsible for in-vitro contraction and relaxation of smooth muscle strips from whole gastro esophageal specimens obtained from organ transplant donors with and without GERD. We compare responses between the following muscle strips: gastric sling muscle fibers, gastric clasp muscle fibers, lower esophageal circular muscle fibers, mid esophageal circular muscle fibers, and longitudinal esophageal muscle fibers. PUBLIC HEALTH RELEVANCE: Gastro esophageal reflux affects at least 40% of the population. Although effective symptomatic acid suppressive treatments for gastroesophageal reflux disease (GERD) are available, they do not prevent reflux of gastric contents. The goal of this proposal is to define the role of the various components of the gastroesophageal high-pressure zone, in particular the gastric sling-clasp fiber complex, in the pathogenesis of GERD.